Figure 1 shows the flow chart of this research.

From January 2014 to January 2024, we retrospectively identified 128 consecutive patients with Waldenström macroglobulinemia (WM) who were diagnosed and treated with CD20-based chemoimmunotherapy at Fujian Medical University Union Hospital, a tertiary referral center. The diagnosis of WM was established according to the World Health Organization (WHO) classification, based on bone marrow biopsy demonstrating lymphoplasmacytic lymphoma in association with any level of IgM monoclonal gammopathy. All bone marrow and, when available, lymph node biopsy specimens were reviewed by at least two experienced hematopathologists in the Department of Pathology at our institution; no additional external centralized pathology review was performed. All enrolled patients had clinically significant tumor burden at diagnosis, manifesting as immune-related cytopenia, hepatosplenomegaly, lymphadenopathy or other WM-related symptoms, and therefore met guideline-recommended indications for initiating chemoimmunotherapy. Eligible patients were required to be ≥18 years of age and to have received at least one cycle of a rituximab-based CD20-targeted regimen as initial treatment or first systemic therapy at our center. According to the different treatment regimens, patients were divided into four groups: fludarabine + cyclophosphamide + rituximab (FCR group, n = 50), bendamustine + rituximab (BR group, n = 58), rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP group, n = 12), and rituximab monotherapy (RTX group, n = 8). Patients who received their primary treatment outside our institution, had insufficient baseline or follow-up data, or were enrolled in interventional clinical trials were excluded. Baseline demographic and disease characteristics are summarized in Table 1, and detailed baseline laboratory parameters are provided in Supplementary Table S1. The study protocol was approved by the Ethics Committee of Fujian Medical University Union Hospital (approval number 2024KY070). Given the retrospective design and the use of anonymized data, the requirement for written informed consent was waived.

Inclusion criteria: (1) Diagnosis of Waldenström Macroglobulinemia (WM) confirmed per the 2016 World Health Organization (WHO) criteria (11). Diagnosis requires integration of clinical manifestations, laboratory tests, and molecular genetic findings. Typical symptoms include chronic fatigue, weight loss, anemia, bleeding tendencies (such as skin ecchymosis), and peripheral neuropathy. Laboratory tests must demonstrate a significant increase in serum IgM levels (usually > 2g/dL), hematological abnormalities (anemia, leukopenia, thrombocytopenia), and lymphoplasmic infiltration confirmed by bone marrow biopsy (confirmed by immunohistochemistry or flow cytometry). Imaging (CT/PET-CT) may reveal splenomegaly or lymph node enlargement. Molecular genetic testing must identify the MYD88 L265P mutation (present in about 86% of patients), CXCR4 mutation (associated with drug resistance), and monoclonal IgM protein detection by immunoelectrophoresis. (2) Receiving at least one standard treatment regimen containing CD20 monoclonal antibody (rituximab) (including FCR, BR, R-CHOP, or monotherapy RTX) with completion of ≥3 treatment cycles; (3) Complete baseline data (including age, stage of IPSSWM, IgM level, proportion of bone marrow infiltration, etc.) and regular follow-up records (survival status, disease progression, adverse events, etc.) for ≥5 years; (4) Age ≥18 years, ability to comply with treatment and follow-up evaluations, and provision of informed consent. Case ascertainment & diagnostic criteria: For patients diagnosed before 2016, all source records were re−abstracted and uniformly reclassified according to the 2016 WHO criteria applied retrospectively. No patient failing 2016 criteria was retained.

Exclusion criteria: (1) History of other active solid tumors or hematological malignancies; (2) Severe cardiac, hepatic or renal insufficiency (e.g. LVEF<50%, ALT/AST>3 times the upper limit of normal, eGFR<30 mL/min/1.73m2) or uncontrollable infection; (3) Failure to complete the prescribed treatment regimen due to drug intolerance, financial constraints, or other reasons, or switching to non-CD20-targeted therapies (e.g., Bruton’s tyrosine kinase [BTK] inhibitors, bortezomib); (4) Pregnant or lactating women, or a documented history of grade ≥3 rituximab hypersensitivity (e.g., anaphylaxis, severe bronchospasm, or hypotension) despite premedication; non−severe infusion reactions alone were not exclusionary.

Physicians chose among FCR, BR, R−CHOP, and rituximab monotherapy based on age, comorbidity burden, IPSSWM risk, tumor bulk (IgM level, marrow infiltration, lymphadenopathy), and frailty. Rituximab monotherapy was generally used in very elderly/frail patients. R−CHOP was reserved for suspected transformation or rapid cytoreduction needs (e.g., B symptoms, high LDH, high Ki−67, or high PET SUVmax), acknowledging that anthracycline−containing regimens are generally considered less preferable for typical WM and should be used cautiously. Management of high baseline IgM and rituximab−flare risk: For baseline IgM >4 g/dL or hyperviscosity, measures included therapeutic plasmapheresis within 24–48 hours when indicated; steroid pre−phase and/or cytoreductive chemotherapy prior to rituximab; deferral of rituximab until viscosity ≤4 cP or ≥50% IgM reduction; and enhanced monitoring during the first two infusions.

The treatment plan of this study strictly adhered to the National Comprehensive Cancer Network (NCCN) guidelines and the consensus of Chinese WM diagnosis and treatment experts (12). The specific medication plan of each group was as follows:

All CD20-targeted regimens in this cohort used rituximab as the anti-CD20 monoclonal antibody component; no patients received obinutuzumab or other second-generation anti-CD20 antibodies during the study period.

Baseline clinical features were collected using the electronic medical record system, including age, international prognostic scoring system for WM (IPSSWM), immunoglobulin M (IgM) levels, bone marrow infiltration percentage, and gene mutation status. Treatment response data (overall response rate [ORR], complete response rate [CRR]) and long-term follow-up information (overall survival [OS], progression-free survival [PFS], and relapse-related mortality) were also recorded.

Overall survival (OS) was defined as the time from diagnosis of WM to death from any cause or last follow-up, and progression-free survival (PFS) was defined as the time from initiation of the index CD20-based regimen to documented disease progression, relapse, or death, whichever occurred first. Patients who were alive without documented progression at the time of last contact were censored at that date. Patients who were lost to follow-up were censored at the date of last documented clinical assessment. OS and PFS were estimated using the Kaplan–Meier method, and survival curves were compared between treatment groups using the log-rank test. Continuous variables were compared using the t test or Wilcoxon rank-sum test, as appropriate, and categorical variables were compared using the chi-square or Fisher’s exact test.

We initially considered fitting multivariable Cox proportional hazards models to identify independent predictors of OS and PFS; however, the number of death and progression events was limited, particularly in the smaller treatment groups, and several key baseline covariates were missing in a non-negligible proportion of patients. In view of the high risk of overfitting and unstable estimates under these conditions, we chose to present descriptive Kaplan–Meier curves and univariable log-rank p values as our primary survival analyses.

A total of 128 patients with WM were included in the study, and the median follow-up duration was 6.20 ± 2.33 years. At baseline, the four treatment groups differed significantly with respect to age at diagnosis, splenomegaly, lymphadenopathy, bone marrow infiltration and several other clinical characteristics (all P < 0.05). In terms of disease burden, patients in the R-CHOP group had the highest median serum IgM level (12.04 g/dL) and the greatest proportion of bone marrow involvement (45.18%), consistent with more aggressive disease in this cohort. The distribution of IPSSWM risk categories also varied across the four groups, with a higher proportion of high-risk patients observed in the BR and R-CHOP groups, which likely influenced regimen selection in routine clinical practice.

With respect to molecular characteristics, MYD88 mutations were detected in 110 of 128 patients (85.9%), with similar proportions across the four treatment groups, whereas CXCR4 mutations were present in 40 patients (31.3%), with a numerically higher frequency in the BR and R-CHOP groups. MYD88 wild-type and CXCR4 wild-type cases, including a small number of patients with a double wild-type genotype, were also included in this cohort; however, their numbers were too limited to permit separate subgroup analyses. In exploratory analyses, no clear or consistent association was observed between MYD88 or CXCR4 mutation status and treatment response or survival, although the study was not powered to detect modest genotype-associated differences in outcomes.

These imbalances in baseline demographic, clinical and molecular characteristics were not adjusted for by multivariable methods and may therefore affect subsequent efficacy comparisons. Key baseline demographic and disease characteristics are summarized in Table 1, and more detailed baseline laboratory parameters are presented in Supplementary Table S1.

The FCR group achieved the highest treatment response among the four regimens. The overall objective response rate (ORR) in the FCR group was 90.0% (45/50), compared with 79.3% (46/58) in the BR group, 66.7% (8/12) in the R-CHOP group, and 62.5% (5/8) in the RTX group. The complete response (CR) rate was also highest in the FCR group at 30.0% (15/50), whereas the CR rates in the BR, R-CHOP and RTX groups were 20.7% (12/58), 8.3% (1/12), and 12.5% (1/8), respectively. The partial response (PR) rates were 60.0% (30/50) in the FCR group, 58.6% (34/58) in the BR group, 58.3% (7/12) in the R-CHOP group, and 50.0% (4/8) in the RTX group (Figure 2).

Although the overall ORR did not differ significantly among the four groups, the FCR regimen yielded the highest depth of response as reflected by the superior CR rate. The BR and R-CHOP regimens showed moderate efficacy in patients with higher-risk disease. However, the BR group exhibited a relatively higher recurrence rate, while the R-CHOP group was associated with a markedly higher toxicity burden, which may limit its clinical applicability despite its cytoreductive potential (Figure 3).

The proportion of patients receiving consolidation therapy remained low across all treatment groups, and no statistically significant difference was observed among the four groups (P = 0.567, Figure 4).

The OS of FCR group was (75.86 ± 22.05) months, which was significantly better compared to other groups (P = 0.002). Although the PFS was 39.3 months, the difference was not statistically significant (P = 0.102), possibly due to an insufficient sample size. See Figures 5, 6 for details. Histologic transformation to an aggressive lymphoma was rarely observed in this cohort, and the small number of transformation events precluded meaningful comparative analysis between treatment groups.

Significant differences in treatment safety were observed among the four groups, with the highest incidence of grade ≥3 adverse events was reported in the FCR group (60%), mainly due to bone marrow suppression (50%), including leukopenia (46%) and thrombocytopenia (40%). Bone marrow suppression and infection risk (41.7%) were more prominent in the R-CHOP group, likely due to the intensity of chemotherapy. In contrast, the RTX group demonstrated the best safety profile, with a grade ≥3 adverse event rate of 25%, though its efficacy was limited, suggesting suitability for elderly patients or those with poor tolerance. Combination chemotherapy groups showed higher rates of infection and gastrointestinal symptoms, necessitating close clinical monitoring. The distribution of grade ≥3 adverse events across the four regimens is summarized in Table 2, and additional laboratory safety data are presented in Supplementary Table S1.